This invention is in the field of treating cardiovascular disease, and specifically relates to compounds, compositions and methods for treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.
Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds is shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993); Sitori, Pharmac. Ther., 67,443-47 (1995)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)), Morton et al. (J. Lipid Res. 35, 836-847 (1994)) and Tollefson et al. (Am. J. Physiol., 255, (Endocrinol. Metab. 18, E894-E902 (1988))) describe proteins from human plasma that inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity. Cho et al. (Biochim. Biophys. Acta 1391, 133-144 (1998)) describe a peptide from hog plasma that inhibits human CETP. Bonin et al. (J. Peptide Res., 51, 216-225 (1998)) disclose a decapeptide inhibitor of CETP. A depsipeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., 8, 1277-80 (1998).
There have been several reports of non-peptidic compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629-34 (1995)) describe cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds as CETP inhibitors. Japanese Patent Application No. 10287662-A describes polycyclic, non-amine containing, polyhydroxylic natural compounds possessing CETP inhibition properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine modification reagents as CETP inhibitors. Xia et al. describe 1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6,919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994)) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor. Oomura et al. disclose non-peptidic tetracyclic and hexacyclic phenols as CETP inhibitors in Japanese Patent Application No. 10287662. In WO Patent Application No. 09914204, Sikorski describes 1,2,4-triazolylthiols useful as chlolesteryl ester transfer protein inhibitors.
Some substituted heteroalkylamine compounds are known. In European Patent Application No. 796846, Schmidt et al. describe 2-aryl-substituted pyridines as cholesteryl ester transfer protein inhibitors useful as cardiovascular agents. One substitutent at C3 of the pyridine ring can be an hydroxyalkyl group. In European Patent Application No. 801060, Dow and Wright describe heterocyclic derivatives substituted with an aldehyde addition product of an alkylamine to afford 1-hydroxy-1-amines. These are reported to be xcex23-adrenergic receptor agonists useful for treating diabetes and other disorders. In Great Britain Patent Application No. 2305665, Fisher et al. disclose 3-agonist secondary amino alcohol substituted pyridine derivatives useful for treating several disorders including cholesterol levels and artherosclerotic diseases. In European Patent Application No. 818448, Schmidt et al. describe tetrahydroquinoline derivatives as cholesteryl ester transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused heterocycles as cholesteryl ester transfer protein inhibitors. Brandes et al. in German Patent Application No. 19627430 describe bicyclic condensed pyridine derivatives as cholesteryl ester transfer protein inhibitors. In WO Patent Application No. 09839299, Muller-Gliemann et al. describe quinoline derivatives as cholesteryl ester transfer protein inhibitors. U.S. Pat. No. 2,700,686, issued to Dickey and Towne, describes N-(2-haloalkyl-2-hydroxyethyl)amines in which the amine is further substituted with either 1 to 2 aliphatic groups or one aromatic group and one aliphatic group. U.S. Pat. No. 2,700,686 further describes a process to prepare the N-(2-haloalkyl-2-hydroxyethyl)amines by reacting halogenated-1,2-epoxyalkanes with the corresponding aliphatic amines and N-alkylanilines and their use as dye intermediates.
The present invention provides a class of compounds that can be used to inhibit cholesteryl ester transfer protein (CETP) activity and that have the general structure: 
In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
In another aspect, this invention relates to methods of using these inhibitors as therapeutic agents in humans to inhibit cholesteryl ester transfer protein (CETP) activity, thereby decreasing the concentrations of low density lipoprotein (LDL) and raising the level of high density lipoprotein (HDL), resulting in a therapeutically beneficial plasma lipid profile. The compounds and methods of this invention can also be used to treat dyslipidemia (hypoalphalipoproteinemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinemia), peripheral vascular disease, hypercholesterolaemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. The compounds can also be used in prophylactic treatment of subjects who are at risk of developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of this invention would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals such as primates, rabbits, pigs, horses, and the like.
The present invention relates to a class of compounds comprising substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines which are beneficial in the therapeutic and prophylactic treatment of coronary artery disease as given in Formula I-WA (also referred to herein as xe2x80x9calicyclic/cyclic aryl/heteroaryl heteroalkylaminesxe2x80x9d): 
or a pharmaceutically-acceptable salt thereof, wherein;
n is an integer selected from 1 through 4;
A and Q are independently selected from the group consisting of xe2x80x94CH2(CR37R38)vxe2x80x94(CR33R34)uxe2x80x94Txe2x80x94(CR35R36)wxe2x80x94H, 
with the provisos that one of A and Q must be AQ-1 and that one of A and Q must be selected from the group consisting of AQ-2 and xe2x80x94CH2(CR37R38)vxe2x80x94(CR33R34)uxe2x80x94Txe2x80x94(CR35R36)wxe2x80x94H;
T is selected from the group consisting of a single covalent bond, O, S S(O), S(O)2, C(R33)xe2x95x90C(R35), and Cxe2x89xa1C;
v is an integer selected from 0 through 1 with the proviso that v is 1 when any one of R33, R34, R35, and R36 is aryl or heteroaryl;
u and w are integers independently selected from 0 through 6;
A1 is C(R30);
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C, C(R30), N, O, S and a covalent bond with the provisos that no more than 5 of B1, B2, D3, D4, J3, J4 and K2 are a covalent bond, no more than two of B1, B2, D3, D4, J3, J4 and K2 are O, no more than two of B1, B2, D3, D4, J3, J4 and K2 are S, no more than two of B1, B2, D3, D4, J3, J4 and K2 are simultaneously O and S, and no more than two of B1, B2, D3, D4, J3, J4 and K2 are N;
B1 and D3, D3 and J3, J3 and K2, K2 and J4, J4 and D4, and D4 and B2 are independently selected to form an in-ring spacer pair wherein said spacer pair is selected from the group consisting of C(R33)xe2x95x90C(R35) and Nxe2x95x90N with the provisos that AQ-2 must be a ring of at least five contiguous members, that no more than two of the group of said spacer pairs are simultaneously C(R33)xe2x95x90C(R35), and that no more than one of the group of said spacer pairs can Nxe2x95x90N unless the other spacer pairs is other than C(R33)xe2x95x90C(R35), O, N, and S;
R16 is selected from the group consisting of hydrido, alkyl, acyl, aroyl, heteroaroyl, and trialkylsilyl;
X is selected from the group consisting of O, H, F, S, S(O), NH, N(OH), N(alkyl), and N(alkoxy) with the proviso that there is no R16 wherein X is H or F;
R1 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;
R2 is selected from the group consisting of hydrido, aryl, aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, and carboalkoxycyanoalkyl;
R3 is selected from the group consisting of hydrido, hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl, carboxamide, and carboxamidoalkyl;
Y is selected from a group consisting of a covalent single bond, (C(R14)2)q wherein q is an integer selected from 1 through 4 and (CH(R14))gxe2x80x94Oxe2x80x94(CH(R14))p wherein g and p are integers independently selected from 0 through 2;
R14 is selected from the group consisting of hydrido, hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, carboxamidoalkyl;
Z is selected from the group consisting of covalent single bond, (C(R15)2)q wherein q is an integer selected from 1 through 2, and (CH(R15))jxe2x80x94Oxe2x80x94(CH(R15))k wherein j and k are integers independently selected from 0 through 2;
R15 is selected from the group consisting of hydrido, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
R30 is selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso that R30 is selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R30, when bonded to A1, is taken together to form an intra-ring linear spacer connecting the A1-carbon at the point of attachment of R30 to the point of bonding of a group selected from the group consisting of R10, R11, R12, R31, and R32 wherein said intra-ring linear spacer is selected from the group consisting of a covalent single bond and a spacer moiety having from 1 through 6 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 10 contiguous members, a cycloalkenyl having from 5 through 10 contiguous members, and a heterocyclyl having from 5 through 10 contiguous members;
R30, when bonded to A1, is taken together to form an intra-ring branched spacer connecting the A1-carbon at the point of attachment of R30 to the points of bonding of each member of any one of substituent pairs selected from the group consisting of substituent pairs R10 and R11, R10 and R31, R10 and R32, R10 and R12, R11 and R31, R11 and R32, R11 and R12, R31 and R32, R31 and R12, and R32 and R12 and wherein said intra-ring branched spacer is selected to form two rings selected from the group consisting of cycloalkyl having from 3 through 10 contiguous members, cycloalkenyl having from 5 through 10 contiguous members, and heterocyclyl having from 5 through 10 contiguous members;
R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylaridocarbonylamido, arylanidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl with the provisos that R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R31, R32, R33, R34, R35, and R36 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen, that no more than three of the R33 and R34 substituents are simultaneously selected from other than the group consisting of of hydrido and halo, and that no more than three of the R35 and R36 substituents are simultaneously selected from other than the group consisting of of hydrido and halo;
R9, R10, R11, R12, R13, R31, and R32 are independently selected to be oxo with the provisos that B1, B2, D3, D4, J3, J4 and K2 are independently selected from the group consisting of C and S, no more than two of R9, R10, R11, R12, R13, R31, and R32 are simultaneously oxo, and that R9, R10, R11, R12, R13, R31, and R32 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R4 and R5, R5 and R6, R6 and R7, R7 and R8, R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the provisos that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, are used at the same time and that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R11, R11 and R31, R31 and R32, R32 and R12, and R12 and R13 are used at the same time;
R9 and R11, R9 and R12, R9 and R13, R9 and R31, R9 and R32, R10 and R12, R10 and R13, R10 and R31, R10 and R32, R11 and R12, R11 and R13, R11 and R32, R12 and R31, R13 and R31, and R13 and R32 are independently selected to form a spacer pair wherein said spacer pair is taken together to form a linear spacer moiety selected from the group consisting of a covalent single bond and a moiety having from 1 through 3 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl having from 3 through 8 contiguous members, a cycloalkenyl having from 5 through 8 contiguous members, a saturated heterocyclyl having from 5 through 8 contiguous members and a partially saturated heterocyclyl having from 5 through 8 contiguous members with the provisos that no more than one of said group of spacer pairs is used at the same time;
R37 and R38 are independently selected from the group consisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
In another embodiment of compounds of Formula I-WA, compounds are alcohols and have the Formula I-WO (also referred to herein as xe2x80x9calicyclic/cyclic aryl/heteroaryl aminoalkanolsxe2x80x9d): 
or a pharmaceutically acceptable salt thereof, wherein;
R16 is hydrido;
R1, R2, R3, n, A, Y, Q, and Z are defined as given above for Formula I-WA.
In a more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOPA: 
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of hydrido and halo;
R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
R33, R34, R35, and R36 are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOPC: 
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of hydrido and halo;
R9 and R13 is halo;
R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
R10, R11, R12, R31, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
In another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOHA: 
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, and C3-C8 hydroxyhaloalkyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of hydrido and halo;
R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
R33, R34, R35, and R36 are independently selected from the group group consisting of alkyl, halo, hydroxy, cyano, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl.
In still another more specific embodiment of compounds of Formula I-WO, compounds have the Formula I-WOHC: 
or a pharmaceutically acceptable salt thereof, wherein;
n is an integer selected from 1 through 2;
A is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one of D1, D2, J1, J2 and K1 is a covalent bond, no more than one of D1, D2, J1, J2 and K1 is O, no more than one of D1, D2, J1, J2 and K1 is S, one of D1, D2, J1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are O and S, and no more than four of D1, D2, J1, J2 and K1 are N;
R1 is selected from the group consisting of haloalkyl and haloalkoxymethyl;
R2 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, and heteroaryl;
R3 is selected from the group consisting of hydrido, aryl, alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy and alkylene;
R4 and R8 are independently selected from the group consisting of hydrido and halo;
R9 and R13 is halo;
R5, R6, and R7 are independently selected from the group consisting of hydrido, alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R4 and R5, R5 and R6, R6 and R7, and R7 and R8 are independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R4 and R5, R5 and R6, R6 and R7, and R7 and R8, is used at the same time;
R10, R11, R12, R31, and R32 are independently selected from the group group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, alkylthio, arylamino, arylthio, aroyl, arylsulfonyl, aryloxy, aralkoxy, heteroaryloxy, alkoxy, aralkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkanoyl, heteroaryl, cycloalkyl, haloalkylthio, hydroxyhaloalkyl, heteroaralkoxy, heterocyclyloxy, aralkylaryl, heteroaryloxyalkyl, heteroarylthio, and heteroarylsulfonyl;
R30 is selected from the group consisting of alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl.
In a preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,
n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, vinyl, phenyl, 4-trifluoromethylphenyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3,3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, ethyl, vinyl, trifluoromethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
Y and Z are independently selected from the group consisting of a covalent single bond, oxy, and methylene with the proviso that only one of Y and Z are simultaneously oxy;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5 is selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5 isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5 isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R6 is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
In a more preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,
n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, 1,1,2,2-tetrafluoroethoxymethyl, trifluoromethoxymethyl, difluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is selected from the group consisting of hydrido, methyl, ethyl, phenyl, 4-trifluoromethylphenyl, trifluoromethoxymethyl,
1,1,2,2-tetrafluoroethoxymethyl, difluoromethyl, pentafluoroethyl, trifluoromethyl, and 2,2,3,3,3-pentafluoropropyl;
R3 is selected from the group consisting of hydrido, phenyl, 4-trifluoromethylphenyl, methyl, trifluoromethyl, difluoromethyl, and chlorodifluoromethyl;
Y and Z are independently selected from a covalent single bond and methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5 is selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R6 is selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R7 is selected from the group consisting of hydrido, fluoro, and trifluoromethyl.
In an even more preferred specific embodiment of compounds of Formulas I-WOPA, I-WOHA, I-WOPC, and I-WOHC,
n is the integer 1;
R1 is selected from the group consisting of trifluoromethyl, chlorodifluoromethyl, and pentafluoroethyl;
R2 is hydrido, pentafluoroethyl, and trifluoromethyl;
R3 is selected from the group consisting of hydrido, methyl, trifluoromethyl, and difluoromethyl
Y and Z are independently selected from the group consisting of a covalent single bond and methylene;
R4 and R8 are independently selected from the group consisting of hydrido and fluoro;
R5 is selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R6 is selected from the group consisting of fluoro and hydrido;
R7 is selected from the group consisting of hydrido and fluoro.
In a preferred specific embodiment of compounds of Formulas I-WOPA and I-WOHA,
A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2-sec-butoxyethyl, 2-pentoxyethyl, 2-hexoxyethyl, 3-methoxypropyl, 2-methoxyisopropyl, 3-ethoxypropyl, 2-ethoxyisopropyl, 3-propoxypropyl, 2-propoxyisopropyl, 3-isopropoxypropyl, 2-isopropoxyisopropyl, 3-butoxypropyl, 2-butoxyisopropyl, 3-isobutoxypropyl, 2-isobutoxyisopropyl, 3-pentoxypropyl, and 2-pentoxyisopropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R33, R34, R35, and R36 are independently selected from the group consisting of cyano, hydroxy, 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio.
In a preferred specific embodiment of compounds of Formulas I-WOPA and I-WOHA,
A is selected from the group consisting of ethyl, 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-4-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R33, R34, R35, and R36 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio.
In an even more preferred specific embodiment of compounds of Formulas I-WOPA and I-WOHA,
A is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-butyl-3-butenyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group A may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of A to Z with one or more of the group consisting of R33, R34, R35, and R36 with the provisos that R33, R34, R35, and R36 must not be attached to the carbon directly linking A to Z and that R33, R34, R35, and R36 must be selected from other than aryl and heteroaryl when substituting the carbon 2 atoms from Z wherein Z is a single covalent bond;
R33, R34, R35, and R36 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy.
In a preferred specific embodiment of compounds of Formulas I-WOHA and 1-WOHC.
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5 isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5 isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5, triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, 1-indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6.
In a more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC,
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1-indolizinyl, 7-indolizinyl, 1-isoquinolyl, and 2-quinolyl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7. and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6.
In an even more preferred specific embodiment of compounds of Formulas I-WOHA and I-WOHC,
D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond to form the group consisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a ring carbon atom adjacent to the carbon atom at the point of attachment may be optionally substituted with R4 or R8, a ring carbon atom adjacent to the R4 position and two atoms from the point of attachment may be substituted with R5, a ring carbon atom adjacent to the R8 position and two atoms from the point of attachment may be substituted with R7, and a ring carbon atom three atoms from the point of attachment and adjacent to the R5 and R7 positions may be substituted with R6.
In a preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC,
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3-en-4-yl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooctenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2H-2-pyranyl, 2H-3-pyranyl, 2H-4-pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one-4-yl, 2H-pyran-2-one-5-yl, 4H-pyranone-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R9 and R13 are fluoro;
R10 and R12 are independently selected from the group consisting of 4-aminophenoxy, benzoyl, benzyl, benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-bromo-2-nitrophenoxy, 3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromophenoxy, 5-bromopyrid-2-yloxy, 4-butoxyphenoxy, chloro, 3-chlorobenzyl, 2-chlorophenoxy, 4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 3-chloro-4-fluorobenzyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorobenzyloxy, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 4-cyanophenoxy, cyclobutoxy, cyclobutyl, cyclohexoxy, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropyl, cyclopropylmethoxy, cyclopropoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyl, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 2,2-dimethylpropoxy, 1,3-dioxan-2-yl, 1,4-dioxan-2-yl, 1,3-dioxolan-2-yl, ethoxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, fluoro, 4-fluoro-3-methylbenzyl, 4-fluoro-3-methylphenyl, 4-fluoro-3-methylbenzoyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-fluoropyrid-2-yloxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, 3-iodobenzyloxy, isobutyl, isobutylamino, isobutoxy, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, isopropyl, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxycarbonylbutoxy, 3-methoxycarbonylprop-2-enyloxy, 4-methoxyphenyl, 3-methoxyphenylamino, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenzyloxy, 3-methylphenoxy, 3-methylmethylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 4-nitrophenylthio, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, phenylsulfonyl, 4-propanoylphenoxy, propoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, sec-butyl, 4-sec-butylphenoxy, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiophen-2-yl, 2,3,5-trifluorobenzyloxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, and trifluoromethylthio;
R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, trifluoromethyl, and trifluoromethoxy;
R30 is selected from the group consisting of chloro, ethoxy, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isobutoxy, isopropoxy, isopropyl, isopropylthio, methyl, propyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, propoxy, sec-butyl, tert-butoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
In a more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC,
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon may be optionally substituted with R30, a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R9 and R13 are fluoro;
R10 and R12 are independently selected from the group consisting of benzyloxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 3-bromobenzyloxy, 4-bromophenoxy, 4-butoxyphenoxy, 3-chlorobenzyloxy, 2-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 4-chlorophenoxy, 3-chloro-4-ethylphenoxy, 3-chloro-4-methylphenoxy, 3-chloro-4-fluorophenoxy, 4-chloro-3-fluorophenoxy, 4-chlorophenylamino, 5-chloropyrid-3-yloxy, cyclobutoxy, cyclobutyl, cyclohexylmethoxy, cyclopentoxy, cyclopentyl, cyclopentylcarbonyl, cyclopropylmethoxy, 2,3-dichlorophenoxy, 2,4-dichlorophenoxy, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl, 3,4-dichlorophenoxy, 3,4-difluorophenoxy, 2,3-difluorobenzyloxy, 3,5-difluorobenzyloxy, difluoromethoxy, 3,5-difluorophenoxy, 3,4-difluorophenyl, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethoxyphenoxy, 3-dimethylaminophenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 1,3-dioxolan-2-yl, 3-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylbenzyl, 4-fluorobenzyloxy, 2-fluoro-3-methylphenoxy, 3-fluoro-4-methylphenoxy, 3-fluorophenoxy, 3-fluoro-2-nitrophenoxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 2-furyl, 3-furyl, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, 2-hydroxy-3,3,3-trifluoropropoxy, isobutoxy, isobutyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, isopropoxy, 3-isopropylbenzyloxy, 3-isopropylphenoxy, isopropylthio, 4-isopropyl-3-methylphenoxy, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-methoxybenzyl, 4-methoxyphenylamino, 3-methylbenzyloxy, 4-methylbenxyloxy, 3-methylphenoxy, 3-methyl-4-methylthiophenoxy, 4-methylphenoxy, 1-methylpropoxy, 2-methylpyrid-5-yloxy, 4-methylthiophenoxy, 2-naphthyloxy, 2-nitrophenoxy, 4-nitrophenoxy, 3-nitrophenyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, pentafluoroethyl, pentafluoroethylthio, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, phenoxy, phenylamino, 1-phenylethoxy, 4-propylphenoxy, 4-propoxyphenoxy, thiophen-3-yl, tert-butoxy, 3-tert-butylphenoxy, 4-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, tetrahydrofuran-2-yl, 2-(5,6,7,8-tetrahydronaphthyloxy), thiazol-2-yl, thiazolyl, thiazol-5-yl, thiophen-2-yl, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-2-hydroxypropyl, trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, 3-trifluoromethylbenzyl, 3,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylphenyl, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3,4,5-trimethylphenoxy, 3-difluoromethoxyphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 3-trifluoromethylthiophenoxy, 3-trifluoromethylthiobenzyloxy, and trifluoromethylthio;
R11, R31, and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl;
R30 is selected from the group consisting of chloro, ethyl, fluoro, heptafluoropropyl, 1,1,1,3,3,3-hexafluoropropyl, isobutyl, isopropyl, methyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,3,3,3-pentafluoropropyl, 1,1,2,2,3-pentafluoropropyl, propyl, sec-butyl, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethyl, trifluoromethoxy, and trifluoromethyl.
In an even more preferred specific embodiment of compounds of Formulas I-WOPC and I-WOHC,
A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbornyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein a ring carbon other than the ring carbon at the point of attachment of A to Z may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment may be substituted with R12, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position may be substituted with R11, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position may be substituted with R32, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R11 and R32 positions may be substituted with R31;
R9 and R13 are fluoro;
R10 and R12 are independently selected from the group consisting of 5-bromo-2-fluorophenoxy, 4-chloro-3-ethylphenoxy, cyclopentyl, 2,3-dichlorophenoxy, 3,4-dichlorophenoxy, 3-difluoromethoxyphenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3-ethylphenoxy, 3-ethyl-5-methylphenoxy, 4-fluoro-3-methylphenoxy, 4-fluorophenoxy, 2-furyl, isobutyl, isopropoxy, 3-isopropylphenoxy, 3-methylphenoxy, pentafluoroethyl, 3-pentafluoroethylphenoxy, 3-tert-butylphenoxy, 1,1,2,2-tetrafluoroethoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, 2-(5,6,7,8-tetrahydronaphthyloxy), trifluoromethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, trifluoromethyl, 3-trifluoromethylbenzyloxy, 1,1-bis-trifluoromethyl-1-hydroxymethyl, trifluoromethylthio, and 3-trifluoromethylthiophenoxy;
R11, R31 and R32 are independently selected from the group consisting of chloro, fluoro, hydrido, pentafluoroethyl, 1,1,2,2-tetrafluoroethoxy, and trifluoromethyl.
The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol xe2x80x9cCxe2x80x9d represents a carbon atom. The symbol xe2x80x9cOxe2x80x9d represents an oxygen atom. The symbol xe2x80x9cNxe2x80x9d represents a nitrogen atom. The symbol xe2x80x9cPxe2x80x9d represents a phosphorus atom. The symbol xe2x80x9cSxe2x80x9d represents a sulfur atom. The symbol xe2x80x9cHxe2x80x9d represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.).
As utilized herein, the term xe2x80x9calkylxe2x80x9d, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d and xe2x80x9calkylthioxe2x80x9d, means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
The term xe2x80x9calkynylxe2x80x9d refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a xe2x80x9chydroxylxe2x80x9d radical, one hydrido radical may be attached to a carbon atom to form a xe2x80x9cmethinexe2x80x9d radical (xe2x95x90CHxe2x80x94), or two hydrido radicals may be attached to a carbon atom to form a xe2x80x9cmethylenexe2x80x9d (xe2x80x94CH2xe2x80x94) radical.
The term xe2x80x9ccarbonxe2x80x9d radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
The term xe2x80x9ccyanoxe2x80x9d radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term xe2x80x9chydroxyalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
The term xe2x80x9calkanoylxe2x80x9d embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
The term xe2x80x9calkylenexe2x80x9d radical denotes linear or branched radicals having from 1 about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, ethylidene, methylethylene, and isopropylidene.
The term xe2x80x9calkenylenexe2x80x9d radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH2xe2x95x90C), 1,2-vinylidene (xe2x80x94CHxe2x95x90CHxe2x80x94), and 1,4-butadienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94).
The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are xe2x80x9clower haloalkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term xe2x80x9chydroxyhaloalkylxe2x80x9d embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of xe2x80x9chydroxyhaloalkylxe2x80x9d radicals include hexafluorohydoxypropyl.
The term xe2x80x9chaloalkylene radicalxe2x80x9d denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are xe2x80x9clower haloalkylenexe2x80x9d radicals having one to about six carbon atoms. Examples of xe2x80x9chaloalkylenexe2x80x9d radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term xe2x80x9chaloalkenylxe2x80x9d denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term xe2x80x9calkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d and xe2x80x9chaloalkoxyalkylxe2x80x9d radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
The terms xe2x80x9calkenyloxyxe2x80x9d and xe2x80x9calkenyloxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term xe2x80x9calkenyloxyalkylxe2x80x9d also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are xe2x80x9clower alkenyloxyxe2x80x9d radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The xe2x80x9calkenyloxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkenyloxyxe2x80x9d radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.
The term xe2x80x9chaloalkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term xe2x80x9chaloalkenyloxyxe2x80x9d also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term xe2x80x9chaloalkenyloxyalkylxe2x80x9d also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term xe2x80x9calkylenedioxyxe2x80x9d radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of xe2x80x9calkylenedioxyxe2x80x9d radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term xe2x80x9chaloalkylenedioxyxe2x80x9d radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of xe2x80x9chaloalkylenedioxyxe2x80x9d radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term xe2x80x9cfusedxe2x80x9d means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term xe2x80x9cfusedxe2x80x9d is equivalent to the term xe2x80x9ccondensedxe2x80x9d. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The term xe2x80x9cperhaloarylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of xe2x80x9cheteroarylxe2x80x9d radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.: unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said xe2x80x9cheterocyclylxe2x80x9d group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. xe2x80x9cAlkylsulfonylalkylxe2x80x9d, embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. xe2x80x9cHaloalkylsulfonylxe2x80x9d, embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. xe2x80x9cHaloalkylsulfonylalkylxe2x80x9d, embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9caminosulfonylxe2x80x9d denotes an amino radical attached to a sulfonyl radical.
The term xe2x80x9csulfinylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals xe2x80x94S(O)xe2x80x94. xe2x80x9cAlkylsulfinylxe2x80x9d, embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. xe2x80x9cAlkylsulfinylalkylxe2x80x9d, embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. xe2x80x9cHaloalkylsulfinylxe2x80x9d, embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. xe2x80x9cHaloalkylsulfinylalkylxe2x80x9d, embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
The term xe2x80x9cheteroaralkylxe2x80x9d embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term xe2x80x9cperhaloaralkylxe2x80x9d embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
The term xe2x80x9caralkylsulfinylxe2x80x9d, embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. xe2x80x9cAralkylsulfinylalkylxe2x80x9d, embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caralkylsulfonylxe2x80x9d, embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. xe2x80x9cAralkylsulfonylalkylxe2x80x9d, embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9ccycloalkylxe2x80x9d embraces radicals having from 3 through 15 carbon atoms. Cycloalkyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkyl radicals having two or more rings include adamantyl, norbornyl, and 7-oxabicyclo[2.2.1]heptanyl. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having from 3 through 8 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9ccycloalkylxe2x80x9d also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals. The term xe2x80x9ccycloalkylalkylxe2x80x9d embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are xe2x80x9clower cycloalkylalkylxe2x80x9d radicals having cycloalkyl radicals attached to alkyl radicals having from one through six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term xe2x80x9ccycloalkenylxe2x80x9d embraces radicals having three to fifteen carbon atoms and one or more carbon-carbon double bonds. Cycloalkenyl radicals may contain one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused. Examples of cycloalkenyl radicals having two or more rings include norbornenyl. Preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term xe2x80x9chalocycloalkylxe2x80x9d embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are xe2x80x9clower halocycloalkylxe2x80x9d radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term xe2x80x9chalocycloalkenylxe2x80x9d embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term xe2x80x9ccycloalkoxyxe2x80x9d embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
The term xe2x80x9ccycloalkoxyalkylxe2x80x9d also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The xe2x80x9ccycloalkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chalocycloalkoxyxe2x80x9d and xe2x80x9chalocycloalkoxyalkylxe2x80x9d radicals. The term xe2x80x9ccycloalkylalkoxyxe2x80x9d embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
The term xe2x80x9ccycloalkenyloxyxe2x80x9d embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term xe2x80x9ccycloalkenyloxyalkylxe2x80x9d also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The xe2x80x9ccycloalkenyloxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chalocycloalkenyloxyxe2x80x9d and xe2x80x9chalocycloalkenyloxyalkylxe2x80x9d radicals.
The term xe2x80x9ccycloalkylenedioxyxe2x80x9d radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of xe2x80x9calkylenedioxyxe2x80x9d radicals include 1,2-dioxycyclohexylene.
The term xe2x80x9ccycloalkylsulfinylxe2x80x9d, embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
xe2x80x9cCycloalkylsulfinylalkylxe2x80x9d, embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9cCycloalkylsulfonylxe2x80x9d, embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. xe2x80x9cCycloalkylsulfonylalkylxe2x80x9d, embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9ccycloalkylalkanoylxe2x80x9d embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced, are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having one to six carbon atoms. An example of xe2x80x9clower alkylthioxe2x80x9d is methylthio (CH3xe2x80x94Sxe2x80x94). The xe2x80x9calkylthioxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkylthioxe2x80x9d radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term xe2x80x9calkyl aryl aminoxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.
The terms alkylamino denotes xe2x80x9cmonoalkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d containing one or two alkyl radicals, respectively, attached to an amino radical.
The terms arylamino denotes xe2x80x9cmonoarylaminoxe2x80x9d and xe2x80x9cdiarylaminoxe2x80x9d containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.
The term xe2x80x9caralkylaminoxe2x80x9d, embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes xe2x80x9cmonoaralkylaminoxe2x80x9d and xe2x80x9cdiaralkylaminoxe2x80x9d containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes xe2x80x9cmonoaralkyl monoalkylaminoxe2x80x9d containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term xe2x80x9carylsulfinylxe2x80x9d embraces radicals containing an aryl radical, as defined above, attached to a divalent S(xe2x95x90O) atom. The term xe2x80x9carylsulfinylalkylxe2x80x9d denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term xe2x80x9carylsulfonylxe2x80x9d, embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. xe2x80x9carylsulfonylalkylxe2x80x9d, embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term xe2x80x9cheteroarylsulfinylxe2x80x9d embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(xe2x95x90O) atom. The term xe2x80x9cheteroarylsulfinylalkylxe2x80x9d denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term xe2x80x9cHeteroarylsulfonylxe2x80x9d, embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. xe2x80x9cHeteroarylsulfonylalkylxe2x80x9d, embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloroethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and 3-(1,1,2,2-tetrafluoroethoxy)phenoxy.
The term xe2x80x9caroylxe2x80x9d embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term xe2x80x9caralkanoylxe2x80x9d embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.
The term xe2x80x9caryloxyalkylxe2x80x9d embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
The term xe2x80x9chaloaryloxyalkylxe2x80x9d embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
The term xe2x80x9cheteroaroylxe2x80x9d embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term xe2x80x9cheteroaralkanoylxe2x80x9d embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term xe2x80x9cheteroaralkoxyxe2x80x9d embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are xe2x80x9clower heteroaralkoxyxe2x80x9d radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term xe2x80x9chaloheteroaryloxyalkylxe2x80x9d embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term xe2x80x9cheteroarylaminoxe2x80x9d embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
The term xe2x80x9cheteroarylaminoalkylxe2x80x9d embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.
The term xe2x80x9cheteroaryloxyxe2x80x9d embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.
The term xe2x80x9cheteroaryloxyalkylxe2x80x9d embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
The term xe2x80x9carylthioxe2x80x9d embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
The term xe2x80x9carylthioalkylxe2x80x9d embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
The term xe2x80x9calkylthioalkylxe2x80x9d embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term xe2x80x9ccarbonylxe2x80x9d denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term xe2x80x9ccarboxyxe2x80x9d embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboxamidexe2x80x9d embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboxamidoalkylxe2x80x9d embraces carboxamide radicals, as defined above, attached to an alkyl group. The term xe2x80x9ccarboxyalkylxe2x80x9d embraces a carboxy radical, as defined above, attached to an alkyl group. The term xe2x80x9ccarboalkoxyxe2x80x9d embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9ccarboaralkoxyxe2x80x9d embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term xe2x80x9cmonocarboalkoxyalkylxe2x80x9d embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term xe2x80x9cdicarboalkoxyalkylxe2x80x9d embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term xe2x80x9cmonocyanoalkylxe2x80x9d embraces one cyano radical, as defined above, attached to an alkyl group. The term xe2x80x9cdicyanoalkylenexe2x80x9d embraces two cyano radicals, as defined above, attached to an alkyl group. The term xe2x80x9ccarboalkoxycyanoalkylxe2x80x9d embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.
The term xe2x80x9cacylxe2x80x9d, alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of xe2x80x9cacylxe2x80x9d are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term xe2x80x9chaloalkanoylxe2x80x9d embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl. The term xe2x80x9cdiacylxe2x80x9d, alone or in combination, means having two or more carbonyl or thionocarbonyl groups bonded to a radical selected from, for example, alkylene, alkenylene, alkynylene, haloalkylene, alkoxyalkylene, aryl, heterocyclyl, heteroaryl, aralkyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl. Examples of xe2x80x9cdiacylxe2x80x9d are phthaloyl, malonyl, succinyl, adipoyl, and the like.
The term xe2x80x9cbenzylidenylxe2x80x9d radical denotes substituted and unsubstituted benzyl groups having attachment points for two covalent bonds. One attachment point is through the methylene of the benzyl group with the other attachment point through an ortho carbon of the phenyl ring. The methylene group is designated for attached to the lowest numbered position. Examples include the base compound benzylidene of structure: 
The term xe2x80x9cphenoxylidenylxe2x80x9d radical denotes substituted and unsubstituted phenoxy groups having attachment points for two covalent bonds. One attachment point is through the oxy of the phenoxy group with the other attachment point through an ortho carbon of the phenyl ring. The oxy group is designated for attached to the lowest numbered position. Examples include the base compound phenoxylidene of structure: 
The term xe2x80x9cphosphonoxe2x80x9d embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term xe2x80x9cdialkoxyphosphonoxe2x80x9d denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term xe2x80x9cdiaralkoxyphosphonoxe2x80x9d denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term xe2x80x9cdialkoxyphosphonoalkylxe2x80x9d denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term xe2x80x9cdiaralkoxyphosphonoalkylxe2x80x9d denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
Said xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9calkanoylxe2x80x9d, xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cbenzylidenylxe2x80x9d, xe2x80x9cphenoxylidenylxe2x80x9d, xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkylenexe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkenyloxyxe2x80x9d, xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, xe2x80x9carylxe2x80x9d, xe2x80x9cperhaloarylxe2x80x9d, xe2x80x9chaloalkoxyxe2x80x9d, xe2x80x9chaloalkoxyalkylxe2x80x9d, xe2x80x9chaloalkenyloxyxe2x80x9d, xe2x80x9chaloalkenyloxyalkylxe2x80x9d, xe2x80x9calkylenedioxyxe2x80x9d, xe2x80x9chaloalkylenedioxyxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d, xe2x80x9chydroxyhaloalkylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9chaloalkylsulfonylxe2x80x9d, xe2x80x9calkylsulfonylalkylxe2x80x9d, xe2x80x9chaloalkylsulfonylalkylxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9calkylsulfinylalkylxe2x80x9d, xe2x80x9chaloalkylsulfinylalkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9cheteroaralkylxe2x80x9d, xe2x80x9cperhaloaralkylxe2x80x9d, xe2x80x9caralkylsulfonylxe2x80x9d, xe2x80x9caralkylsulfonylalkylxe2x80x9d, xe2x80x9caralkylsulfinylxe2x80x9d, xe2x80x9caralkylsulfinylalkylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9ccycloalkylalkanoylxe2x80x9d, xe2x80x9ccycloalkylalkylxe2x80x9d, xe2x80x9ccycloalkenylxe2x80x9d, xe2x80x9chalocycloalkylxe2x80x9d, xe2x80x9chalocycloalkenylxe2x80x9d, xe2x80x9ccycloalkylsulfinylxe2x80x9d, xe2x80x9ccycloalkylsulfinylalkylxe2x80x9d, xe2x80x9ccycloalkylsulfonylxe2x80x9d, xe2x80x9ccycloalkylsulfonylalkylxe2x80x9d, xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9ccycloalkoxyalkylxe2x80x9d, xe2x80x9ccycloalkylalkoxyxe2x80x9d, xe2x80x9ccycloalkenyloxyxe2x80x9d, xe2x80x9ccycloalkenyloxyalkylxe2x80x9d, xe2x80x9ccycloalkylenedioxyxe2x80x9d, xe2x80x9chalocycloalkoxyxe2x80x9d, xe2x80x9chalocycloalkoxyalkylxe2x80x9d, xe2x80x9chalocycloalkenyloxyxe2x80x9d, xe2x80x9chalocycloalkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9chaloalkylthioxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d, xe2x80x9caminoxe2x80x9d, xe2x80x9coxyxe2x80x9d, xe2x80x9cthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, xe2x80x9caralkylaminoxe2x80x9d, xe2x80x9carylsulfinylxe2x80x9d, xe2x80x9carylsulfinylalkylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9carylsulfonylalkylxe2x80x9d, xe2x80x9cheteroarylsulfinylxe2x80x9d, xe2x80x9cheteroarylsulfinylalkylxe2x80x9d, xe2x80x9cheteroarylsulfonylxe2x80x9d, xe2x80x9cheteroarylsulfonylalkylxe2x80x9d, xe2x80x9cheteroarylaminoxe2x80x9d, xe2x80x9cheteroarylaminoalkylxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9cheteroaryloxylalkylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caroylxe2x80x9d, xe2x80x9caralkanoylxe2x80x9d, xe2x80x9caralkoxyxe2x80x9d, xe2x80x9caryloxyalkylxe2x80x9d, xe2x80x9chaloaryloxyalkylxe2x80x9d, xe2x80x9cheteroaroylxe2x80x9d, xe2x80x9cheteroaralkanoylxe2x80x9d, xe2x80x9cheteroaralkoxyxe2x80x9d, xe2x80x9cheteroaralkoxyalkylxe2x80x9d, xe2x80x9carylthioxe2x80x9d, xe2x80x9carylthioalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, xe2x80x9cacylxe2x80x9d and xe2x80x9cdiacylxe2x80x9d groups defined above may optionally have 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocyeloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term xe2x80x9cspacerxe2x80x9d may include a covalent bond, a linear moiety having a backbone of 1 to 7 continous atoms, and a branched moiety having three branches connecting to a common atom with a total of from 1 through 8 atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from xe2x95x90C(H)xe2x80x94, xe2x95x90C(R17)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(R17)xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94CH(OH)xe2x80x94, xe2x95x90C(OH)xe2x80x94, xe2x80x94CH(OR17)xe2x80x94, xe2x95x90C(OR17)xe2x80x94, and xe2x80x94C(O)xe2x80x94 wherein R17 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms, a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain, or a branched chain made up of 1 or 2 or 3 or 4 atoms in each of the three branches. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, ethenyl, xe2x80x94CHxe2x95x90CH(OH)xe2x80x94, xe2x80x94OCH2Oxe2x80x94, xe2x80x94O(CH2)2Oxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94OCH(R17)Oxe2x80x94, xe2x80x94O(CH2CHR17)Oxe2x80x94, xe2x80x94OCF2Oxe2x80x94, xe2x80x94O(CF2)2Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(H)xe2x80x94, xe2x80x94N(H)Oxe2x80x94, xe2x80x94N(R17)Oxe2x80x94, xe2x80x94N(R17)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NR17xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, S(O)CH2xe2x80x94, xe2x80x94CH2C(O)xe2x80x94, xe2x80x94CH(OH)xe2x80x94, xe2x95x90C(OH)xe2x80x94, xe2x80x94CH(OR17)xe2x80x94, xe2x95x90C(OR17)xe2x80x94, S(O)2CH2xe2x80x94, and xe2x80x94NR17CH2xe2x80x94 and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 to 5 non-hydrido substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
The terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (xe2x80x9ccisxe2x80x9d) or on opposite sides of the double bond (xe2x80x9ctransxe2x80x9d).
Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the xe2x80x9cketoxe2x80x9d form and in part or principally as one or more xe2x80x9cenolxe2x80x9d forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both xe2x80x9cketoxe2x80x9d and xe2x80x9cenolxe2x80x9d tautomeric forms.
Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the xe2x80x9cketoxe2x80x9d form and in part or principally as one or more xe2x80x9cenolxe2x80x9d forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both xe2x80x9cketoxe2x80x9d and xe2x80x9cenolxe2x80x9d tautomeric forms. Said amide carbonyl groups may be both oxo (Cxe2x95x90O) and thiono (Cxe2x95x90S) in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the xe2x80x9ciminexe2x80x9d form and in part or principally as one or more xe2x80x9cenaminexe2x80x9d forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both xe2x80x9ciminexe2x80x9d and xe2x80x9cenaminexe2x80x9d tautomeric forms.
The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows: xe2x80x9cAAxe2x80x9d represents amino acids, xe2x80x9cBINAPxe2x80x9d represents 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, xe2x80x9cBocxe2x80x9d represents tert-butyloxycarbonyl, xe2x80x9cBOPxe2x80x9d represents benzotriazol-1-yl-oxy-tris-(dimethylamino), xe2x80x9cbuxe2x80x9d represents butyl, xe2x80x9cdbaxe2x80x9d represents dibenzylideneacetone, xe2x80x9cDCCxe2x80x9d represents 1,3-dicyclohexylcarbodiimide, xe2x80x9cDIBAHxe2x80x9d represents diisobutylaluminum hydride, xe2x80x9cDIPEAxe2x80x9d represents diisopropylethylamine, xe2x80x9cDMFxe2x80x9d represents dimethylformamide, xe2x80x9cDMSOxe2x80x9d represents dimethylsulfoxide, xe2x80x9cFmocxe2x80x9d represents 9-fluorenylmethoxycarbonyl, xe2x80x9cLDAxe2x80x9d represents lithium diisopropylamide, xe2x80x9cPHTHxe2x80x9d represents a phthaloyl group, xe2x80x9cpnZxe2x80x9d represents 4-nitrobenzyloxycarbonyl, xe2x80x9cPFCxe2x80x9d represents a phase transfer catalyst, xe2x80x9cp-TsOHxe2x80x9d represents paratoluenesulfonic acid, xe2x80x9cTBAFxe2x80x9d represents tetrabutylammonium fluoride, xe2x80x9cTBTUxe2x80x9d represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, xe2x80x9cTEAxe2x80x9d represents triethylamine, xe2x80x9cTFAxe2x80x9d represents trifluoroacetic acid, xe2x80x9cTHFxe2x80x9d represents tetrahydrofuran, xe2x80x9cTMSxe2x80x9d represents trimethylsilyl, and xe2x80x9cZxe2x80x9d represents benzyloxycarbonyl.
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas VII-H, VII, VII-2, VII-3, VII-4, and Cyclo-VII, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula I-WA: 
wherein R1, R2, R3, n, R14, R15, R16, A, Q, X, Y, and Z are as defined above for the compounds of Formula I-WA;
or a pharmaceutically-acceptable salt thereof.
As a further embodiment, compounds of the present invention of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC, or a pharmaceutically-acceptable salt thereof as defined above and further comprise a treatment and prophylaxis of coronary artery disease and other CETP-mediated disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC, of the present invention or a pharmaceutically-acceptable salt thereof.
Compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are capable of inhibiting activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as peripheral vascular disease, hyperlipidaemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both, or a procedure to study the mechanism of action of the cholesteryl ester transfer protein (CETP) to enable the design of better inhibitors. The compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Also included in the family of compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I-WA may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I-WA include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC by reacting, for example, the appropriate acid or base with the compounds of Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC.
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formula I-WA in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
All mentioned references are incorporated by reference as if here written.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
The compounds of the present invention can be synthesized, for example, according to the following procedures of Schemes 1 through 14 below, wherein the substituents are as defined for Formulas I-WA, I-WO, I-WOHA, I-WOPC, I-WOHA, and I-WOHC above except where further noted.
Synthetic Scheme 1 shows the preparation of compounds of formula XIIIA-H (xe2x80x9cSecondary Heteroaryl Aminesxe2x80x9d) which are intermediates in the preparation of the compounds of the present invention corresponding to Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) wherein one substituent (A or Q) on the nitrogen is AQ-1 which can be independently selected from the group consisting of aryl and heteroaryl, which are preferably substituted with one or more groups, and another substituent (A or Q) on the nitrogen is AQ-2 which can be independently selected from the group consisting of AQ-2 and xe2x80x94CH2(CR37R38)vxe2x80x94(CR33R34)uxe2x80x94Txe2x80x94(CR35R36)wxe2x80x94H. AQ-2 and xe2x80x94CH2(CR37R38)vxe2x80x94(CR33R34)uxe2x80x94Txe2x80x94(CR35R36)wxe2x80x94H can be independently selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein said group may be optionally substituted.
Schemes 1 through 14, taken together, prepare tertiary heteroalkylamine compounds of the present invention by addition of a halogenated, heteroatom (for example, oxygen, sulfur, or nitrogen) containing precursor to a resulting secondary amine to introduce a heteroatom containing alkyl group wherein one of the two groups making up the secondary amine is aromatic groups and the other is aliphatic (for example, C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C6 alkoxy C1-C2 alkyl, C3-C8 hydroxyhaloalkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl), C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl.
The xe2x80x9cHeteroaryl Iminesxe2x80x9d corresponding to Formulas XII-AH, CXII-AH, CKXII-AH can be prepared through dehydration techniques generally known in or adaptable from the art by reacting xe2x80x9cHeteroaryl Aminexe2x80x9d of Formula X-AH or a xe2x80x9cHeteroaryl Carbonylxe2x80x9d of Formula XI-AH with a suitable an aliphatic, saturated heterocyclic, or partially saturated heterocyclic amine or carbonyl compound as shown in Schemes 1, 3, 4, 5, 6, 12, and subsequent specific examples. For example in Scheme 3, the two reactants (AQ-2A and XI-AH) react by refluxing them in an aprotic solvent, such as hexane, toluene, cyclohexane, benzene, and the like, using a Dean-Stark type trap to remove water. After about 2-8 hours or until the removal of water is complete, the aprotic solvent is removed in vacuo to yield the xe2x80x9cHeteroaryl Iminexe2x80x9d of Formula XII-AH.
The xe2x80x9cSecondary Cyclic Heteroaryl Aminesxe2x80x9d of Formula XIIIA-H can be prepared from the corresponding xe2x80x9cGeneric Iminexe2x80x9d of Formula XII, xe2x80x9cCyclic Heteroaryl Iminexe2x80x9d of Formulas XII-AH, CXII-AH, and CKXII-AH can be prepared in several ways. For example, in one synthetic scheme (Reduction Method-1), the xe2x80x9cGeneric Iminexe2x80x9d of Formula XII-AH is partially or completely dissolved in presence of a lower alcohol containing sufficient organic or mineral acid, as described in WO Patent Application No. 9738973, Swiss Patent CH 441366 and U.S. Pat. Nos. 3,359,316 and 3,334,017, which are incorporated herein by reference, and then hydrogenated at 0-100xc2x0 C., more preferably 20-50xc2x0 C., and most preferably between 20-30xc2x0 C. and pressures of 10-200 psi hydrogen or more preferably between 50-70 psi hydrogen in the presence of a noble metal catalyst such as PtO2.
In another synthetic scheme (Reduction Method-2), the xe2x80x9cCyclic Heteroaryl Iminexe2x80x9d of Formulas XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol such as ethanol, methanol or like solvent at 0-10xc2x0 C. and solid sodium borohydride is added in batches over 5-10 minutes at 0-10xc2x0 C. with stirring. The reaction mixture is stirred below 10xc2x0 C. for 30-90 minutes and then is warmed gradually to 15-30xc2x0 C. After about 1-10 hours, the mixture is cooled and acid is added until the aqueous layer was just acidic (pH 5-7).
In yet another synthetic scheme (Reduction Method-3), which is preferred when Z is an oxygen, the xe2x80x9cCyclic Heteroaryl Iminexe2x80x9d of Formulas XII-AH, CXII-AH, and CKXII-AH is slurried in a lower alcohol solvent at 0-10xc2x0 C. and acidified to a pH less than 4 and sodium cyanoborohydride is added in batches over 30-90 minutes at 0-20xc2x0 C. with stirring and addition of a suitable organic or mineral acid to keep the pH at or below 4. The reaction mixture is stirred and warmed gradually to about 20-25xc2x0 C. After about 1-10 hours, the mixture is cooled and base added until the mixture was just slightly alkaline.
The xe2x80x9cSecondary Cyclic Heteroaryl Aminesxe2x80x9d of Formulas XIII-AH, CXIIIA-H, and CKXIII-AH can also be prepared, according to Schemes 1 and 3, by an alkylation procedure based on the nucleophilic substitution of bromides by amines. In one synthetic alkylation scheme (Alkylation Method-1), a xe2x80x9cCyclic Aminexe2x80x9d of Formula AQ-2A or a xe2x80x9cGeneric Amine-Ixe2x80x9d of Formula X is reacted with a xe2x80x9cHeteroaryl Bromidexe2x80x9d of Formula XXI-AH or xe2x80x9cGeneric Bromidexe2x80x9d of Formula XXI as described in Vogel""s Textbook of Practical Organic Chemistry, Fifth Edition, 1989, pages 902 to 905 and references cited therein all of which are incorporated herein by reference. In an alternate synthetic alkylation scheme exemplified in Scheme 1, an xe2x80x9cAminexe2x80x9d of Formula XXII is reacted with a xe2x80x9cHeteroaryl Bromidexe2x80x9d in a method employing palladium catalyzed carbon-nitrogen bond formation. Suitable procedures for this conversion are described in Wagaw and Buchwald, J. Org. Chem.(1996), 61, 7240-7241, Wolfe, Wagaw and Buchwald, J. Am. Chem. Soc. (1996), 118, 7215-7216, and Wolfe and Buchwald, Tetrahedron Letters (1997),38(36), 6359-6362 and references cited therein all of which are incorporated herein by reference.
The xe2x80x9cGeneric Secondary Aminexe2x80x9d, xe2x80x9cHeteroaryl Aminexe2x80x9d, xe2x80x9cCyclic Aminexe2x80x9d, xe2x80x9cAlicyclic Aminexe2x80x9d, and xe2x80x9cHeteoaryl Hydroxylaminexe2x80x9d amines and hydroxylamines, the xe2x80x9cGeneric Carbonylxe2x80x9d, xe2x80x9cHeteroaryl Carbonylxe2x80x9d, xe2x80x9cCyclic Carbonylxe2x80x9d, and xe2x80x9cCyclic Ketonexe2x80x9d aldehydes and ketones, and xe2x80x9cGeneric Bromide-1xe2x80x9d, xe2x80x9cGeneric Bromide-2xe2x80x9d, xe2x80x9cHeteroaryl Bromidexe2x80x9d, and the like halides, tosylates, mesylates, triflates, and precursor alcohols required to prepare the xe2x80x9cSecondary Cyclic Heteroaryl Aminexe2x80x9d compounds are available from commercial sources or can be prepared by one skilled in the art from published procedures. Commercial sources include but are not limited to Aldrich Chemical, TCI-America, Lancaster-Synthesis, Oakwood Products, Acros Organics, and Maybridge Chemical. Disclosed procedures for xe2x80x9cGeneric Aminexe2x80x9d amines, hydroxylamines, and hydrazines include Sheradsky and Nov, J. Chem. Soc., Perkin Trans.1 (1980), (12), 2781-6; Marcoux, Doye, and Buchwald, J. Am. Chem. Soc. (1997), 119, 1053-9; Sternbach and Jamison, Tetrahedron Lett. (1981), 22(35), 3331-4; U.S. Pat. No. 5,306,718; EP No. 314435; WO No. 9001874; WO No. 9002113; JP No. 05320117; WO No. 9738973; Swiss Patent No. CH 441366; U.S. Pat. Nos. 3,359,316 and 3,334,017; and references cited therein which are incorporated herein by reference.
Synthetic Schemes 2, 10 and 11 show the preparation of the class of compounds of the present invention corresponding to Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d).
Derivatives of xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d or xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d, in which the heteroatom (O, N, or S) is attached to an alkyl group removed from the amine by two or more carbons are readily prepared by anion chemistry using the method of Scheme 2. The anion of xe2x80x9cSecondary Aminexe2x80x9d amines and hydroxylamines of Formula XIII are readily formed by dissolving the specific amine, hydroxylamine, or hydrazine in an aprotic solvent, such as tetrahydrofuran, toluene, ether, dimethylformamide, and dimethylformamide, under anhydrous conditions. The solution is cooled to a temperature between xe2x88x9278 and 0xc2x0 C., preferably between xe2x88x9278 and xe2x88x9260xc2x0 C. and the anion formed by the addition of at least one equivalent of a strong, aprotic, non-nucleophillic base such as NaH or n-butyllithium under an inert atmosphere for each acidic group present. Maintaining the temperature between xe2x88x9278 and 0xc2x0 C., preferably between xe2x88x9278 and xe2x88x9260xc2x0 C., with suitable cooling, an appropriate alkyl halide, alkyl benzenesulfonate such as a alkyl tosylate, alkyl mesylate, alkyl triflate or similar alkylating reagent of the general structure: 
where m is zero, X can be RN, O, and S, and M is a readily displaceable group such as chloride, bromide, iodide, tosylate, triflate, and mesylate. After allowing the reaction mixture to warm to room temperature, the reaction product is added to water, neutralized if necessary, and extracted with a water-immiscible solvent such as diethyl ether or methylene chloride. The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d). This material is purified, for example, by eluting through silica gel with a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield purified Formula I-WA and Formula I-WO. Products are structurally confirmed by low and high resolution mass spectrometry and NMR.
Compounds of Formula (XXX), which can be used to prepare I-WA, I-WO, I-WOPA, I-WOPC, I-WOHA, and I-WOHC, are given in Table 2. Reagents 1a and 2a in Table 2 are prepared from the corresponding alcohols. The tosylates are readily obtained by reacting the corresponding alcohol with tosyl chloride using procedures found in House""s Modern Synthetic Reactions, Chapter 7, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons, which are incorporated herein by reference.
A preferred procedure for Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d compounds is Method A of Schemes 2, 10, 11, and 14. Oxirane reagents useful in Method A are exemplified, but not limited to those in Table 1. Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl 1-Amino-2-alcoholxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylaminexe2x80x9d) compounds are prepared by using xe2x80x9cSecondary Cyclic Heteroaryl Aminexe2x80x9d and xe2x80x9cAlicyclic Heteroaryl Aminexe2x80x9d amines and hydroxylamines of Formulas XIIIA-H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with oxiranes of the type listed in Table 1 and represented by the general structure: 
In some cases, the oxiranes are prepared by reaction of epoxidation reagents such as MCPBA and similar type reagents readily selectable by a person of skill-in-the-art with alkenes. Fieser and Fieser in Reagents for Organic Synthesis, John Wiley and Sons provides, along with cited references, numerous suitable epoxidation reagents and reaction conditions, which are incorporated herein by reference.
Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylaminexe2x80x9d) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using appropriate aziridines and thirranes according to Method A of Scheme 2. Aziridine and thiirane reagents useful in Method A are exemplified, but not limited to those in Table 1. These Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary 2-Heteroalkylaminexe2x80x9d) compounds, wherein the 2-hetero group is an amino, substituted amino, or thiol, can be prepared by using xe2x80x9cSecondary Cyclic Heteroaryl Aminexe2x80x9d and xe2x80x9cAlicyclic Heteroaryl Aminexe2x80x9d amines and hydroxylamines of Formulas XIIIA-H, CXIIIA-H, CKXIII-AH, ACXIIIA-H, and RACXIIIA-H prepared above with aziridines and thiiranes of the type listed in Table 1 and represented by the general structure: 
wherein X is selected from N and S and R16 is hydrogen or another suitable group when X is N.
A mixture of a xe2x80x9cSecondary Aminexe2x80x9d amine or hydroxylamine and an oxirane of Formula XX are stirred and heated to 40-90xc2x0 C. for 5 to 48 hours in a tightly capped or contained reaction vessel. A Lewis acid such as ytterbium triflate in acetonitrile may be added to speed up reaction and improve yield. When a Lewis acid is used, the reaction should be carried out under inert, anhydrous conditions using a blanket of dry nitrogen or argon gas. After cooling to room temperature and testing the reaction mixture for complete reaction by thin layer chromatography or high pressure liquid chromatography (hplc), the reaction product is added to water and extracted with a water immiscible solvent such as diethyl ether or methylene chloride. (Note: If the above analysis indicates that reaction is incomplete, heating should be resumed until complete with the optional addition of more of the oxirane). The combined aprotic solvent extract is washed with saturated brine, dried over drying agent such as anhydrous MgSO4 and concentrated in vacuo to yield crude Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds. This material is purified by eluting through silica gel with 5-40% of a medium polar solvent such as ethyl acetate in a non-polar solvent such as hexanes to yield the Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds. Products are tested for purity by HPLC. If necessary, the Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds are purified by additional chromatography or recrystallization. Products are structurally confirmed by low and high resolution mass spectrometry and NMR. Examples of specific Formula VII Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) prepared are summarized in the Examples and Example Tables 1 through 7.
Specific Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) analogs of the Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds summarized in the Examples and Example Tables 1 through 7, wherein the hydroxyl or oxy group are replaced with an amino, substituted amino, aza, or thiol, can be prepared by using the appropriate aziridine reagents or thiirane reagents readily by adapting the procedures in the numerous specific Examples and Schemes disclosed in the present invention. Similarly, intermediates, in which the hydroxyl or oxy group of said intermediates are replaced with an amino, substituted amino, aza, or thiol, can be converted using the numerous specific Examples and Schemes disclosed in the present invention to other Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds.
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds can further be prepared in an alternate manner to procedures disclosed above and in Schemes 1, 2, and 3. Schemes 12 and 13 detail such procedures to prepare compounds of the present invention by initial formation of an halogenated, oxygen containing primary alkylamine XL (xe2x80x9cGeneric Substituted Alkylaminexe2x80x9d). Said halogenated, oxygen containing primary alkylamine XL, formed in Scheme 12, is itself converted to secondary amine LX-H (xe2x80x9cHeteroaryl Alkyl Amine) using procedures disclosed above. Primary alkylamine XL is first reacted with an aldehydic or ketonic carbonyl compound, XI-AH (xe2x80x9cHeteroaryl Carbonylxe2x80x9d) with azeotropic distillation to form imines, L-H (xe2x80x9cHeteroaryl Iminexe2x80x9d). Said imine L-H are then reduced with or without prior isolation by Reduction Methods 1, 2 or 3 as disclosed above and in Scheme I to yield secondary amines LX-H (xe2x80x9cHeteroaryl Alkyl Amine). Said secondary amine LX-H can be converted according to Scheme 14 to Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d).
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds can further be prepared in an alternate manner to procedures disclosed above and in additional Schemes.
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) are alternately referred to as Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl 2-hydroxyalkylaminesxe2x80x9d).
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds can themselves serve as intermediates for conversion to additional compounds of this invention. Compounds of the present invention useful as intermediates include those in which the R5 or R7 position substituent in Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) compounds is a bromo group, hydroxyl-group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other preferred compounds of the present invention useful as intermediates include those in which the R10 position substituent in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups. Other compounds of Formulas I-WA or I-WO and the present invention useful as intermediates include those in which one or more of R6, R11, and R12 substituents in Formulas I-WA or I-WO is a bromo group, hydroxyl group, sulfhydryl group, bromomethyl or other bromoalkyl groups, nitro group, amino group, methoxy carbonyl or other alkoxy carbonyl groups, cyano group, or acyl groups.
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) are alternately referred to as Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Tertiary 2-hydroxyalkylaminesxe2x80x9d).
A 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d) can be reacted with a phenol to afford 3-phenoxy compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
A 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoheteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) can, be reacted, for example, with a phenol to afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
A 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) can be reacted with a phenol to afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a primary or secondary amine can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-R22aminoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Phenylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-bromo substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a heteroaryl dibutyl tin compound can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Heteroarylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-bromomethyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Bromomethylaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl borinate can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Arylmethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl bromide or heteroaryl bromide can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aryloxyaryl, 3-Heteroaryloxyaryl, 3-Heteroaryloxyheteroaryl, and 3-Aryloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aryl bromide can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Phenoxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxyheteroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aralkyl bromide or heteroaralkyl bromide can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aralkyloxyaryl, 3-Heteroaralkyloxyaryl, 3-Heteroaralkyloxyheteroaryl, and 3-Aralkyloxyheteroaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d).
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an aralkyl bromide can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aralkyloxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-hydroxyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic Polycyclic 3-Hydroxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Organooxyaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-thio substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-thioaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with a displaceable organo bromide can afford additional compounds of the present invention of Formula 1-WO (xe2x80x9cAlicyclic/Cyclic 3-Organothiaaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). xe2x80x9cAlicyclic/Cyclic 3-Organothiaaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d can be oxidized to sulfonyl compounds of 3-Organosulfonylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-nitro substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Nitroaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by hydrogenation can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aminoaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d) can be acylated to acyl amide compounds of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Acylaminoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-amino substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Aminoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with carbonyl compounds can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-(Saturated Nitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d and xe2x80x9cAlicyclic/Cyclic 3-(Unsaturated Nitrogen Heterocycl-1yl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-cyano substituent at the R5 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Cyanoaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with organometallic reagents can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Acylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d). Said xe2x80x9cAlicyclic/Cyclic 3-Acylaryl Tertiary 2-Hydroxyalkylaminesxe2x80x9d, can be reduced to hydroxyl compounds of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxysubstitutedmethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with amination reagents can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carboxamidoaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an organometallic reagent can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-(bis-Organohydroxymethyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with lithium aluminum hydride can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Hydroxymethylaryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction with an alkylation reagent can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-(bis-Organo-hydroxymethyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Conversion of a 3-methoxycarbonyl substituent at the R10 position in Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-Carbomethoxyaryl Tertiary 2-hydroxyalkylaminexe2x80x9d) by reaction intially with an amidation reagent and then an organometallic reagent can afford additional compounds of the present invention of Formula I-WO (xe2x80x9cAlicyclic/Cyclic 3-(Organo-carbonyl)aryl Tertiary 2-Hydroxyalkylaminexe2x80x9d).
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) and other compounds of this invention poss-sessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. The hydroxyl group X, wherein R16 is a hydrogen, of compounds of the present invention can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. In like manner, compounds that have at least one hydroxyl group present in the form of an alcohol or phenol can be acylated to its corresponding esters. Similarly, carbamic acid esters (urethans) can be obtained by reacting any hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA, I-WO, and other compounds of the present invention that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide. Suitable procedures and methods for preparing these derivatives can be found in House""s Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and other compounds of the present invention are available from commerical sources or the references cited above, which are incorporated herein by reference.
Formula I-WO (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl Aminoalcoholsxe2x80x9d) and Formula I-WA (xe2x80x9cAlicyclic/Cyclic Aryl/Heteroaryl tertiary Heteroalkylaminesxe2x80x9d) and other compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. The hydroxyl group X, wherein R16 is a hydrogen, of compounds of Formulas I-WA, I-WO, and other compounds of the present invention can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate.
The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. In like manner, compounds of Formulas I-WA, I-WO, and the like that have at least one hydroxyl group present in the form of an alcohol or phenol can be alkylated to their corresponding ethers. Compounds of Formulas I-WA, I-WO, and other compounds that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formulas I-WA, I-WO, and other compounds that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods 1, 2, or 3 as shown in Scheme 1. Suitable procedures and methods for preparing these derivatives can be found in House""s Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Indentification of Organic Compounds, 5th Edition, John Wiley and Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley and Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formulas I-WA, I-WO, and the like are available from commerical sources or the references cited above, which are incorporated herein by reference.
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. 
The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by 1H NMR and mass spectrometry. These compounds also may be formed in vivo.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula V-H. These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.